The present invention is directed to novel taxanes which have utility as antileukemia and antitumor agents.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has a 2xe2x80x2R, 3xe2x80x2S configuration and the following structural formula: 
wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
Colin et al. reported in U.S. Pat. No. 4,814,470 that taxol derivatives having structural formula (2) below, have an activity significantly greater than that of taxol (1). 
Rxe2x80x2 represents hydrogen or acetyl and one of Rxe2x80x3 and Rxe2x80x2xe2x80x3 represents hydroxy and the other represents tert-butoxy-carbonylaminlo and their stereoisomeric forms, and mixtures thereof. The compound of formula (2) in which Rxe2x80x2 is hydrogen, Rxe2x80x3 is hydroxy, Rxe2x80x2xe2x80x3 is tert-butoxycarbonylamino having the 2xe2x80x2R, 3xe2x80x2S configuration is commonly referred to as taxotere.
Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents.
Among the objects of the present invention, therefore, is the provision of novel taxane derivatives which are valuable antileukemia and antitumor agents.
Briefly, therefore, the present invention is directed to taxane derivatives having a C13 side chain which includes an alkoxy or alkenoxy substituent, but which differs from taxotere with respect to at least one substituent. In a preferred embodiment, the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula: 
wherein
X1 is xe2x80x94OX6, xe2x80x94SX7, or xe2x80x94NX8X9;
X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 and X4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X5 is xe2x80x94COOX10;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X9 is an amino protecting group;
X10 is alkyl, alkenyl or aryl;
R1 is hydrogen, hydroxy, protected hydroxy, or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, xe2x80x94OCOR31 or together with R2a forms an oxo;
R2a is hydrogen or taken together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, xe2x80x94OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo,
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo,
R7a is hydrogen, halogen, protected hydroxy, xe2x80x94OR28, or together with R7 forms an oxo;
R9 is hydrogen or together with R9a forms an oxo,
R9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R9 forms an oxo;
R10 is hydrogen or together with R10a forms an oxo,
R10a is hydrogen, xe2x80x94OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R28 is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative;
R29, R30, and R31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl, provided, however, that when X10 is t-butyl at least one of said other X1-X9 or R1-R31 has a value such that the structure of the taxane is different from that of taxotere.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.